This paper attempts to address the challenges of how to invest in Synthetic Biology firms, most of which are relatively new start-ups and unprofitable. Valuing an early-stage firm with only a brief ... [more ▼]

This paper attempts to address the challenges of how to invest in Synthetic Biology firms, most of which are relatively new start-ups and unprofitable. Valuing an early-stage firm with only a brief operating history, little or no operating profit (or even revenue), and an immature and untested business model, could be a formidable challenge. We propose a limited number of quantitative, and a larger number of qualitative criteria. An investor may consider these when faced with analyzing a new untried business, but one he/she believes has considerable potential for success in the future. [less ▲]

BACKGROUND: Elevated resting heart rate is associated with worse outcomes in chronic heart failure (HF) but little is known about its prognostic impact in acute setting. The main aim of the present study ... [more ▼]

BACKGROUND: Elevated resting heart rate is associated with worse outcomes in chronic heart failure (HF) but little is known about its prognostic impact in acute setting. The main aim of the present study was to examine the relationship between resting heart rate obtained 24-36h after admission for acute non-arrhythmic HF and in-hospital mortality. METHODS AND RESULTS: We examined the association of heart rate with in-hospital mortality in a cohort of 712 patients admitted for acute HF. None of the patients had significant arrhythmias, required invasive ventilation, or presented with acute coronary syndrome or primary valvular disease. Forty patients (5.6%) died during the hospital stay. Those patients were significantly older (78+/-9 vs. 72+/-12years; p=0.0021), had higher heart rate (92+/-22 vs. 78+/-18bpm; p<0.0001), NT pro-BNP (p=0.0005), creatinine (p=0.023), were often diabetics (p=0.026) and had lower systolic and diastolic blood pressures (p<0.05). There was a significant graded relationship between the increase in mortality rate and tertile of heart rate (p<0.01). With multivariable analysis, age (p=0.037), heart rate (p<0.0001), diastolic blood pressure (p<0.001), prior ischemic heart disease (p=0.02) and creatinine (p=0.019) emerged as independent predictors of in-hospital mortality. After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worst outcomes when compared with those in the lowest heart rate group (p=0.007). CONCLUSIONS: Higher heart rate 24-36h after admission for acute non-arrhythmic HF is associated with increased risk of in-hospital mortality. Early targeting of elevated heart rate might represent a complementary therapeutic challenge. [less ▲]

Pulmonary hypertension (PH) is a classic pathophysiological consequence of left-sided valvular heart disease (VHD). However, as opposed to other forms of PH, there are relatively few published data on the ... [more ▼]

Pulmonary hypertension (PH) is a classic pathophysiological consequence of left-sided valvular heart disease (VHD). However, as opposed to other forms of PH, there are relatively few published data on the prevalence, impact on outcome, and management of PH with VHD. The objective of this paper is to present a systematic review of PH in patients with VHD. PH is found in 15% to 60% of patients with VHD and is more frequent among symptomatic patients. PH is associated with higher risk of cardiac events under conservative management, during valve replacement or repair procedures, and even following successful corrective procedures. In addition to its usefulness in assessing the presence and severity of VHD, Doppler echocardiography is a key tool in diagnosis of PH and assessment of its repercussion on right ventricular function. Assessment of pulmonary arterial pressure during exercise stress echocardiography may provide additional prognostic information beyond resting evaluation. Cardiac magnetic resonance is also useful for assessing right ventricular geometry and function, which provide additional prognostic information in patients with VHD and PH. [less ▲]

The study of spatial patterns is of ecological importance in order to understand the causes of the distribution and abundance of organisms, and it also provides valuable basis for management and ... [more ▼]

The study of spatial patterns is of ecological importance in order to understand the causes of the distribution and abundance of organisms, and it also provides valuable basis for management and conservation. Amphipod crustaceans are key organisms in seagrass ecosystems. However, little attention has been paid to the spatial scales at which amphipod assemblages may vary. We examined variability patterns of amphipod populations inhabiting Posidonia oceanica meadows, over spatial scales spanning four orders of magnitude (1 to 1000 metres) and for two consecutive years. This study reports the scales that contributed most to spatial variation of amphipod assemblages and explores the potential processes of the observed patterns, with particular emphasis on habitat features. The number of species, the diversity and the density of some species, exhibited high variation across years. Most species showed the highest spatial variation in density and biomass at small scales (~1 and 10 m). Based on density data, the structure of amphipod assemblages did not differ at any scales investigated. The patchiness that occurred at small scales may have been only weakly related to habitat features. Instead, we postulated that behavioural processes of amphipods were likely good explanatory factors. Although, the small scale spatial variability can be an important feature of amphipod assemblages in P. oceanica meadows, many patterns probably remained undetected as they may occur at scales smaller than those investigated. [less ▲]

AIM: The aim of this study is to determine the prevalence and evolution of anaemia in prospectively followed children and adolescents diagnosed with Crohn's disease (CD). METHODS: The BELCRO registry ... [more ▼]

AIM: The aim of this study is to determine the prevalence and evolution of anaemia in prospectively followed children and adolescents diagnosed with Crohn's disease (CD). METHODS: The BELCRO registry (inclusion May 2008-April 2010), describing current clinical treatment practice of children diagnosed with CD, provided data on age, height, body mass index (BMI), paediatric Crohn's disease activity index (PCDAI), therapy and haemoglobin (Hb) at diagnosis 12 and 24 months follow-up. Anaemia was defined as Hb < -2 sd, while severe anaemia was defined as Hb < -4 sd. Patients were classified as child </=13 and adolescent >13 years of age. RESULT: Ninety-six were included, 13 dropped out due to insufficient Hb data (37 females/46 males; median age 13.3 years, range 2.2-17.8 years). At diagnosis, the median Hb sd was -2.66 (-8.4; 1.07) and was correlated with the PCDAI (p = 0.013). At diagnosis, 51/83 (61 %) were anaemic and all had active disease. Hb z-score significantly improved (p < 0.0001) but 26/68 (38 %) remained anaemic at 12 months and 29/76 (38 %) at 24 months of follow-up. The correlation to the PCDAI disappeared. At 24 months, children were more likely to be anaemic. There was no difference in iron dose nor duration of iron supplements between children and adolescents. Iron treatment was more readily given to patients presenting with anaemia. Hb did not differ between patients with (n = 28) or without iron supplements. Half of the patients with persisting anaemia were given iron supplements, of which, only three were given intravenously. CONCLUSION: Anaemia remains an important extra-intestinal manifestation of CD in children. Physicians, lacking optimal treatment strategies, undertreat their patients. [less ▲]

BACKGROUND & AIMS: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for ... [more ▼]

BACKGROUND & AIMS: There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for measuring disease progression. We developed the Lemann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohn's disease (CD). METHODS: We performed a prospective, multicenter, international, cross-sectional study of patients with CD evaluated at 24 centers in 15 countries. Inclusions were stratified based on CD location and duration. All patients underwent clinical examination and abdominal magnetic resonance imaging analyses. Upper endoscopy, colonoscopy, and pelvic magnetic resonance imaging analyses were performed according to suspected disease locations. The digestive tract was divided into 4 organs and subsequently into segments. For each segment, investigators collected information on previous operations, predefined strictures, and/or penetrating lesions of maximal severity (grades 1-3), and then provided damage evaluations ranging from 0.0 (no lesion) to 10.0 (complete resection). Overall level of organ damage was calculated from the average of segmental damage. Investigators provided a global damage evaluation (from 0.0 to 10.0) using calculated organ damage evaluations. Predicted organ indexes and Lemann Index were constructed using a multiple linear mixed model, showing the best fit with investigator organ and global damage evaluations, respectively. An internal cross-validation was performed using bootstrap methods. RESULTS: Data from 138 patients (24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively) were analyzed. According to validation, the unbiased correlation coefficients between predicted indexes and investigator damage evaluations were 0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, anus, respectively, and 0.84 overall. CONCLUSIONS: In a cross-sectional study, we assessed the ability of the Lemann Index to measure cumulative structural bowel damage in patients with CD. Provided further successful validation and good sensitivity to change, the index should be used to evaluate progression of CD and efficacy of treatment. [less ▲]

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a quality by design (QbD) approach, there have been many discussions on the opportunity for ... [more ▼]

Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a quality by design (QbD) approach, there have been many discussions on the opportunity for analytical procedure developments to follow a similar approach. While development and optimization of analytical procedure following QbD principles have been largely discussed and described, the place of analytical procedure validation in this framework has not been clarified. This article aims at showing that analytical procedure validation is fully integrated into the QbD paradigm and is an essential step in developing analytical procedures that are effectively fit for purpose. Adequate statistical methodologies have also their role to play: such as design of experiments, statistical modelling, and probabilistic statements. The outcome of analytical procedure validation is also an analytical procedure design space, and from it, control strategy can be set. [less ▲]

The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior ... [more ▼]

The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior knowledge gathered during pharmaceutical development studies to provide a scientific rationale for the manufacturing process of a product and provide guarantee of future quality. This poses several challenges from a statistical standpoint and requires a shift in paradigm from traditional statistical practices. First, to provide “assurance of quality” of future lots implies the need to make predictions regarding the quality given past evidence and data. Second, the quality attributes described in the Q8 guidelines are not always a set of unique, independent measurements. In many cases, these criteria are com- plicated longitudinal data with successive acceptance criteria over a defined period of time. A common example is a dissolution profile for a modified or extended-release solid dosage form that must fall within acceptance limits at several time points. A Bayesian approach for longitudinal data obtained in various conditions of a design of experiment is provided to elegantly address the ICH-Q8 recommendation to provide assurance of quality and derive a scientifically sound design space. [less ▲]

Known as a genus of great socio-cultural and economical importance, Guibourtia Benn. includes morphologically very similar multipurpose sister species, found in various habitats with different climate and ... [more ▼]

Known as a genus of great socio-cultural and economical importance, Guibourtia Benn. includes morphologically very similar multipurpose sister species, found in various habitats with different climate and soil conditions. In many places, Guibourtia is subject to local overexploitation by forest companies and local communities. As the population density of Guibourtia species is generally very low, it may be necessary to conduct scientific investigations that will provide valuable information for the management of the populations concerned. This paper is based on an extensive literature review and summarizes the available information on the genus Guibourtia, in terms of botany, ecology, genetics, forestry and ethnobotany. Our review provided evidence that, to date, ecological and silvicultural knowledge regarding Guibourtia species is lacking and that it is very difficult to morphologically differentiate very similar sister species. In addition, we provide a new determination key for the genus Guibourtia. Based on the available information, it is difficult to assess the conservation status of these taxa. Further investigations are needed to suggest appropriate management strategies for Guibourtia. Moreover, species diversity within this genus and its distribution in various tropical biomes make it an excellent biological model for understanding the historical, biological and environmental mechanisms that explain the diversity of tropical moist forests. [less ▲]

Plant-based recombinant protein production systems have gained an extensive interest over the past few years, because of their reduced cost and relative safety. Although the first products are now ... [more ▼]

Plant-based recombinant protein production systems have gained an extensive interest over the past few years, because of their reduced cost and relative safety. Although the first products are now reaching the market, progress are still needed to improve plant hosts and strategies for biopharming. Targeting recombinant proteins toward the extracellular space offers several advantages in terms of protein folding and purification, but degradation events are observed, due to endogenous peptidases. This paper focuses on the analysis of extracellular proteolytic activities in two production systems: cell cultures and root-secretion (rhizosecretion), in Arabidopsis thaliana and Nicotiana tabacum. Proteolytic activities of extracellular proteomes (secretomes) were evaluated in vitro against two substrate proteins: bovine serum albumin (BSA) and human serum immunoglobulins G (hIgGs). Both targets were found to be degraded by the secretomes, BSA being more prone to proteolysis than hIgGs. The analysis of the proteolysis pH-dependence showed that target degradation was mainly dependent upon the production system: rhizosecretomes contained more peptidase activity than extracellular medium of cell suspensions, whereas variations due to plant species were smaller. Using class-specific peptidase inhibitors, serine and metallopeptidases were found to be responsible for degradation of both substrates. An in-depth in silico analysis of genomic and transcriptomic data from Arabidopsis was then performed and led to the identification of a limited number of serine and metallo-peptidases that are consistently expressed in both production systems. These peptidases should be prime candidates for further improvement of plant hosts by targeted silencing. [less ▲]

The novel Rosario Tijeras (Jorge Franco Ramos, 1999) is interpreted here from the perspective of the literary genre of the whodunnit. More particularly, the analysis investigates who is responsible for ... [more ▼]

The novel Rosario Tijeras (Jorge Franco Ramos, 1999) is interpreted here from the perspective of the literary genre of the whodunnit. More particularly, the analysis investigates who is responsible for the murder of the female assassin. Taking into account the serious psychological instability of the narrator and the violations of the maxims of communicative cooperation, it is argued that he is an unreliable narrator. Such a reading of the novel as a detective story told by an unreliable narrator reveals a number of clues as to who murdered Rosario Tijeras. It also paves the way towards a new interpretation of the novel: this article argues that there is a parallelism between Franco Ramos’ novel and La virgen de los Sicarios (1994) by Fernando Vallejo: in both novels the issues of violence and guilt in societies dominated by drug trafficking are treated in a similar way. [less ▲]

Basal cell carcinoma is the most frequent skin cancer. Even though metastases are exceptional, these cancers may be locally highly aggressive. The Hedgehog signaling pathway plays a significant role in ... [more ▼]

Basal cell carcinoma is the most frequent skin cancer. Even though metastases are exceptional, these cancers may be locally highly aggressive. The Hedgehog signaling pathway plays a significant role in the pathogenesis of basal cell carcinoma. Vismodegib is a selective inhibitor of this pathway and may be administered orally. Its main indication is locally advanced basal cell carcinoma, when other therapeutic options have failed or are contra-indicated. Vismodegib can also be used as prophylactic therapy in the Gorlin syndrome or basal cell nevomatosis. Its principal adverse effects are muscle spasms, alopecia and altered taste. They are frequent, but often moderate in intensity; they sometimes restrict continuation of treatment. Two clinical cases are presented, relating the efficacity and tolerance of this new therapeutic option. [less ▲]

We examined the mechanisms involved in the development of the easily learned, easily remembered (ELER) heuristic in three groups of young children (4–5 years, 6–7 years, and 8–9 years). A trial-to ... [more ▼]

We examined the mechanisms involved in the development of the easily learned, easily remembered (ELER) heuristic in three groups of young children (4–5 years, 6–7 years, and 8–9 years). A trial-to-acquisition procedure was used to evaluate how much these children’s judgment of learning depended on the ELER heuristic. Moreover, a new experimental paradigm, composed of six phases—a pretest, four training phases, and a posttest—was employed to implicitly influence the validity of the ELER association that underlies this metacognitive rule. Results revealed that the ELER heuristic develops early (4–5 years), but its use is reduced after implicit training. Furthermore, executive monitoring was found to account for the smaller changes observed in older children (8–9 years) after training. From a developmental perspective, these findings present a coherent picture of children’s learning of metacognitive heuristics, wherein early automatic and implicit learning is later followed by effortful control. [less ▲]